UMLS:C0028754 - FACTA Search

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Query: UMLS:C0028754 (obesity)
124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ductal adenocarcinoma of the pancreas is characterized by extremely aggressive behavior, with an overall 5-year survival of <4%. Because conventional and specifically tailored therapeutic regimens have little impact on patient survival, epidemiological and molecular research aims at identifying and reducing risk factors. Cigarette smoking, obesity, diabetes mellitus, and chronic pancreatitis are amenable to medical prevention or therapy. Heavy alcohol consumption is an inconsistent single risk factor for pancreatic cancer but may promote carcinogenesis by increasing the risk of diabetes mellitus or chronic pancreatitis. For various agents, the key carcinogenic effect is probably an inflammatory response in the pancreatic tissue. On the molecular level, mutations of oncogenes and tumor suppressor genes, as well as various epigenetic alterations, such as overexpression of growth factors and their receptors, are important in tumorigenesis. Complete and safe surgical resection, together with adjuvant therapy, offers prolonged survival, with 5-year survival rates of approximately 25%. However, for unresectable or disseminated disease, which constitutes the vast majority of cases, treatment is palliative. Despite increasing knowledge about the molecular pathology of pancreatic cancer and despite advances in treatment, the overall course of the disease is dismal, and reinforced efforts to reduce incidence and improve outcome are needed desperately.
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PMID:Update on pancreatic cancer and alcohol-associated risk. 1695 77

It is unclear whether body mass index (BMI) and physical activity are associated with the risk of pancreatic cancer in Asian populations. We examined these associations in the Japanese Collaborative Cohort Study for Evaluation of Cancer Risk. Our cohort study included 110,792 Japanese men and women at enrollment (1988-1990). Data on height, body weight (at baseline and at age 20 years) and physical activity were obtained from a questionnaire. Cox proportional hazards models were used to estimate the relative risks of pancreatic cancer mortality. We observed a total of 402 pancreatic cancer deaths during the follow-up period. Men with a BMI of 30 or more at age 20 years had a 3.5-fold greater risk compared with men with a normal BMI. Women with a BMI of 27.5-29.9 at baseline had approximately 60% increased risk compared with women with a BMI of 20.0-22.4. In men, weight loss of 5 kg or more between 20 years of age and baseline age was associated with an increased risk of pancreatic cancer death. In contrast, women with weight loss of 5 kg or more over the same period had a decreased risk. Physical activity was not associated with pancreatic cancer risk in either men or women. Obesity in young adulthood may be associated with an increased risk of death from pancreatic cancer in Japanese men. The risk of pancreatic cancer in relation to BMI seems to differ according to sex and the period over which BMI was measured.
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PMID:Obesity, physical activity and the risk of pancreatic cancer in a large Japanese cohort. 1730 5

WNT signals are context-dependently transduced to canonical and non-canonical signaling cascades. We cloned and characterized wild-type human WNT10B, while another group cloned aberrant human WNT10B with Gly60Asp amino-acid substitution. Proto-oncogene WNT10B is expressed in gastric cancer, pancreatic cancer, breast cancer, esophageal cancer, and cervical cancer. Because WNT10B blocks adipocyte differentiation, coding SNP of WNT10B gene is associated with familial obesity. In 2001, we reported WNT10B upregulation by TNFalpha. Here, comparative integromics analyses on WNT10B orthologs were performed to elucidate the transcriptional mechanism of WNT10B. Chimpanzee WNT10B and cow Wnt10b genes were identified within NW_001223159.1 and AC150975.2 genome sequences, respectively, by using bioinformatics (Techint) and human intelligence (Humint). Chimpanzee WNT10B and cow Wnt10b showed 98.7% and 95.1% total-amino-acid identity with human WNT10B, respectively. N-terminal signal peptide, 24 Cys residues, two Asn-linked glycosylation sites, and Gly60 of human WNT10B were conserved among mammalian WNT10B orthologs. Transcription start site of human WNT10B gene was 106-bp upstream of NM_003394.2 RefSeq 5'-end. Number of GC di-nucleotide repeats just down-stream of WNT10B transcription start site varied among primates and human population. Comparative genomics analyses revealed that double AP1-binding sites in the 5'-flanking promoter region and NF-kappaB-binding site in intron 3 were conserved among human, chimpanzee, cow, mouse, and rat WNT10B orthologs. Because TNFalpha signaling through TNFR1 and TRADD/RIP/TRAF2 complex activates JUN kinase (JNK) and IkappaB kinase (IKK) signaling cascades, conserved AP1- and NF-kappaB-binding sites explain the mechanism of TNFalpha-induced WNT10B upregulation. TNFalpha-WNT10B signaling loop is the negative feedback mechanism of adipogenesis to prevent obesity and metabolic syndrome. On the other hand, TNFalpha-WNT10B signaling loop is implicated in carcinogenesis. Inhibitors of TNFalpha-WNT10B signaling loop could be utilized for the prevention or treatment of cancer associated with chronic inflammation, such as gastric, liver, breast and pancreatic cancer.
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PMID:AP1- and NF-kappaB-binding sites conserved among mammalian WNT10B orthologs elucidate the TNFalpha-WNT10B signaling loop implicated in carcinogenesis and adipogenesis. 1733 47

Fat intake and obesity are positively correlated with pancreatic cancer in humans. N-nitrosobis(2-oxopropyl)amine (BOP) induces pancreatic ductal adenocarcinomas limited to Syrian golden hamsters, other rodents not being susceptible. In the present study, we found markedly high levels of serum triglycerides (TGs) and total cholesterol (TC) in Syrian golden hamsters, but not C57BL/6 mice, ICR mice, F344 rats and Wistar rats. Consistent with this, lipoprotein lipase (LPL) activities in the liver were lower in hamsters compared with mice and rats. To examine effects of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, on LPL expression, serum lipid levels and pancreatic cancer development, 6-week-old female Syrian golden hamsters were subcutaneously injected with BOP (10 mg/kg body wt) four times in a week and thereafter fed a diet containing 800 p.p.m. pioglitazone for 22 weeks. The treatment elevated LPL mRNA expression in the liver and significantly improved hyperlipidemia with serum levels of TG and TC being decreased to 62 and 71%, respectively, of the control values. Concurrently, the incidence and multiplicity of pancreatic ductal adenocarcinomas were significantly decreased by pioglitazone in comparison with the controls (38 versus 80%, P < 0.01 and 0.55 +/- 0.15 versus 1.37 +/- 0.22, P < 0.01, respectively). The suppression rates were greater in invasive adenocarcinomas than non-invasive ones. The incidence of cholangiocellular carcinomas was also reduced. Thus, suppression of pancreatic adenocarcinoma development by pioglitazone is possibly associated with improvement in the serum lipid profile, and hyperlipidemia could be an enhancing factor for development of pancreatic cancer in hamsters.
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PMID:Suppression of N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamsters by pioglitazone, a ligand of peroxisome proliferator-activated receptor gamma. 1744 4

Recent evidence indicates that obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers, including those of the colon, prostate, and pancreas. Obesity, physical inactivity, visceral adiposity, hyperglycemia, and hyperinsulinemia are relatively consistent risk factors for colon cancer and adenoma. Also, patients with type 2 diabetes mellitus have a higher risk of colon cancer. For prostate cancer, the relationship to obesity appears more complex. Obesity seems to contribute to a greater risk of aggressive or fatal prostate cancer but perhaps to a lower risk of nonaggressive prostate cancer. Furthermore, men with type 2 diabetes mellitus are at lower risk of developing prostate cancer. Long-standing type 2 diabetes increases the risk of pancreatic cancer by approximately 50%. Furthermore, over the past 6 years, a large number of cohort studies have reported positive associations between obesity and pancreatic cancer. Together with data from prediagnostic blood specimens showing positive associations between glucose levels and pancreatic cancer up to 25 years later, sufficient evidence now supports a strong role for diabetes and obesity in pancreatic cancer etiology. The mechanisms for these associations, however, remain speculative and deserve further study. Hyperinsulinemia may be important, but the role of oxidative stress initiated by hyperglycemia also deserves further attention.
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PMID:The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. 1749 13

Using data collected of a large population-based cohort study, we studied the association between anthropometric factors and the risk of pancreatic cancer. Furthermore, we investigated whether these associations differ among microscopically confirmed pancreatic cancer (MCPC) cases and non-MCPC (NMCPC) cases. The Netherlands Cohort Study on Diet and Cancer started in 1986 (120,852 men and women) and uses the case-cohort methodology. After 13.3 years of follow-up, 446 pancreatic cancer cases (of which 65% was microscopically confirmed) and 4,774 subcohort members were available for analysis. The multivariable incidence rate ratio of MCPC of men was 1.10 per increment of 1 kg.m(-2) (95% confidence interval, 1.04-1.18). Women had a rate ratio of MCPC of 1.08 (95% confidence interval, 1.03-1.13). Obese men [body mass index (BMI) >or=30 kg.m(-2)] had a 2.6-fold increased risk of MCPC compared with men with BMI 23 to 25 kg.m(-2). For women, this increase in risk was 1.7-fold. Change in BMI between age 20 years and baseline was also associated with MCPC in both men and women. In men and women, none of these associations were observed for NMCPC, with the exception of the increased risk for pancreatic cancer in obese men. We observed statistically significant associations between both BMI, gain in BMI, and pancreatic cancer risk. These associations are observed only in MCPC and not in NMCPC. If MCPC and NMCPC had been considered as one group, the reported associations would not have been detected. These findings stress the need to evaluate heterogeneity among pancreatic cancer cases in etiologic studies.
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PMID:Anthropometry and pancreatic cancer risk: an illustration of the importance of microscopic verification. 1758 56

Late diagnosis and ineffective therapeutic options mean that pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer. The identification of genetic alterations facilitated the launch of the Pancreatic Intraepithelial Neoplasm nomenclature, a standardized classification system for pancreatic duct lesions, but the factors that contribute to the development of such lesions and their progression to high-grade neoplasia remain obscure. Age, smoking, obesity and diabetes confer increased risk of PDA, and the presence of chronic pancreatitis is a consistent risk factor for pancreatic cancer. It is hypothesized that chronic inflammation generates a microenvironment that contributes to malignant transformation in the pancreas, as is known to occur in other organs. Pancreatic stellate cells (PSCs) are the main mediator of fibrogenesis during chronic pancreatitis, but their contribution to the development of PDA has not been elucidated. Data now suggest that PSCs might assume a linking role in inflammation-associated carcinogenesis through their ability to communicate with inflammatory cells, acinar cells, and pancreatic cancer cells in a complicated network of interactions. In this Review, the role of PSCs in the process of inflammation-associated carcinogenesis is discussed and new potential treatment options evaluated.
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PMID:Mechanisms of disease: chronic inflammation and cancer in the pancreas--a potential role for pancreatic stellate cells? 1766 94

Gastrin and cholecystokinin (CCK) are two of the oldest hormones and within the past 15 years there has been an exponential increase in knowledge of their pharmacology, cell biology, receptors (CCK1R and CCK2R), and roles in physiology and pathological conditions. Despite these advances there is no approved disease indication for CCK receptor antagonists and only a minor use of agonists. In this review, the important factors determining this slow therapeutic development are reviewed. To assess this it is necessary to briefly review what is known about the roles of CCK receptors (CCK1R and CCK2R) in normal human physiology, their role in pathologic conditions, the selectivity of available potent CCKR agonists/antagonists as well as to review their use in human conditions to date and the results. Despite extensive studies in animals and in humans, recent studies suggest that monotherapy with CCK1R agonists will not be effective in obesity, nor CCK2R antagonists in panic disorders or CCK2R antagonists to inhibit growth of pancreatic cancer. Areas that require more study include the use of CCK2R agonists for imaging tumors and radiotherapy, CCK2R antagonists in hypergastrinemic states especially with long-term PPI use and for potentiation of analgesia as well as use of CCK1R antagonists for a number of gastrointestinal disorders [motility disorders (irritable bowel syndrome, dyspepsia, and constipation) and pancreatitis (acute and chronic)].
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PMID:Progress in developing cholecystokinin (CCK)/gastrin receptor ligands that have therapeutic potential. 1799 37

Obesity and lack of physical activity have been inconsistently associated with pancreatic cancer. Using data from a self-administered baseline questionnaire (1995-1996), the authors investigated the association between adiposity and physical activity and pancreatic cancer in 495,035 participants of the National Institutes of Health-AARP Diet and Health Study who were aged 50-71 years. To avoid the influence of subclinical disease, follow-up time started 1 year after baseline, and subjects with a body mass index (BMI) of <18.5 kg/m(2) were excluded. A subcohort (n = 302,060) completed a second questionnaire with information about physical activity and waist and hip circumference. During follow-up though 2000, 654 pancreatic cancer cases were identified. The authors used Cox proportional hazard models to generate adjusted hazard ratios and 95% confidence intervals. Compared with those with a BMI of 18.5-<25, those with a BMI of >/=35 had a 45% greater pancreatic cancer risk (95% confidence interval (CI): 1.04, 2.02; p(trend) = 0.02). Significant positive associations for BMI were observed among nonsmokers (for BMI > or =35: hazard ratio = 1.70, 95% CI: 1.14, 2.53; p(trend) = 0.004) but not recent smokers (p(interaction) = 0.08). Waist circumference was positively associated with pancreatic cancer (fourth vs. first quartile: hazard ratio = 2.53, 95% CI: 1.13, 5.65; p(trend) = 0.04) in women but not men. The authors observed no association with physical activity. Their results suggest a positive association between adiposity and pancreatic cancer.
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PMID:Adiposity, physical activity, and pancreatic cancer in the National Institutes of Health-AARP Diet and Health Cohort. 1827 Mar 73

Obesity has become epidemic in the United States, in Europe, and in many urban areas in the developing world. The globalization of certain 'fast foods' and 'soft drinks' may, in part, be contributing to this epidemic. Diets high in saturated fatty acids and trans fats as well as drinks that have high fructose corn syrup levels may be particularly harmful. Recent research suggests that fat is a dynamic endocrine organ and that visceral fat is associated with the metabolic syndrome. Central obesity leads to organ steatosis and altered serum adipokines including reduced adiponectin and markedly elevated leptin. This abnormal adipokine milieu results in increased tissue infiltration of monocytes and macrophages which produce proinflammatory cytokines that alter organ function. Over many years, the combination of steatosis and local inflammation leads to fibrosis and eventually to cancer. Nonalcoholic fatty liver disease (NAFLD) is a precursor for nonalcoholic steatohepatitis (NASH). NAFLD and NASH (1) lead to cirrhosis and hepatocellular carcinoma, (2) increase the risk of liver resection, and (3) compromise the outcome of liver transplantation. Similarly, in the pancreas nonalcoholic fatty pancreas disease (NAFPD) may lead to nonalcoholic steatopancreatitis (NASP). NAFPD and NASP may (1) promote the development of chronic pancreatitis and pancreatic cancer, (2) exacerbate the severity of acute pancreatitis, and (3) increase the risk of pancreatic surgery. In the gallbladder nonalcoholic fatty gallbladder disease (NAFGBD, cholecystosteatosis) may lead to steatocholecystitis. Cholecystosteatosis may be an explanation for (1) the increased incidence of chronic acalculous cholecystitis and (2) the increased number of cholecystectomies.
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PMID:Hepato-pancreato-biliary fat: the good, the bad and the ugly. 1833 22

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